University of Pittsburgh

About: University of Pittsburgh is a education organization based out in Pittsburgh, Pennsylvania, United States. It is known for research contribution in the topics: Population & Transplantation. The organization has 87042 authors who have published 201012 publications receiving 9656783 citations. The organization is also known as: Pitt & Western University of Pennsylvania.

Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors

Abstract: Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascades. The release mechanisms include interactions of B-cell/lymphoma 2 family proteins with a mitochondria-specific phospholipid, cardiolipin, to cause permeabilization of the outer mitochondrial membrane. Using oxidative lipidomics, we showed that cardiolipin is the only phospholipid in mitochondria that undergoes early oxidation during apoptosis. The oxidation is catalyzed by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. In a previously undescribed step in apoptosis, we showed that oxidized cardiolipin is required for the release of proapoptotic factors. These results provide insight into the role of reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation.

Differential Effect of Stress on In Vivo Dopamine Release in Striatum, Nucleus Accumbens, and Medial Frontal Cortex

Abstract: Microdialysis was used to assess extracellular dopamine in striatum, nucleus accumbens, and medial frontal cortex of unanesthetized rats both under resting conditions and in response to intermittent tail-shock stress. The dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid also were measured. The resting extracellular concentration of dopamine was estimated to be approximately 10 nM in striatum, 11 nM in nucleus accumbens, and 3 nM in medial frontal cortex. In contrast, the resting extracellular levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid were in the low micromolar range. Intermittent tail-shock stress increased extracellular dopamine relative to baseline by 25% in striatum, 39% in nucleus accumbens, and 95% in medial frontal cortex. 3,4-Dihydroxyphenylacetic acid and homovanillic acid also were generally increased by stress, although there was a great deal of variability in these responses. These data provide direct in vivo evidence for the global activation of dopaminergic systems by stress and support the concept that there exist regional variations in the regulation of dopamine release.

A Controlled Trial of Fluconazole to Prevent Fungal Infections in Patients Undergoing Bone Marrow Transplantation

Abstract: Background and Methods. Superficial and systemic fungal infections are a major problem among severely immunocompromised patients who undergo bone marrow transplantation. We performed a doubleblind, randomized, multicenter trial in which patients receiving bone marrow transplants were randomly assigned to receive placebo or fluconazole (400 mg daily). Fluconazole or placebo was administered prophylactically from the start of the conditioning regimen until the neutrophil count returned to 1000 per microliter, toxicity was suspected, or a systemic fungal infection was suspected or proved. Results. By the end of the treatment period, 67.2 percent of the 177 patients assigned to placebo had a positive fungal culture of specimens from any site, as compared with 29.6 percent of the 179 patients assigned to fluconazole. Among these, superficial infections were diagnosed in 33.3 percent of the patients receiving placebo and in 8.4 percent of the patients receiving fluconazole (P<0.001). Systemic fungal in...

The Treatment of Non-LTE Line Blanketing in Spherically Expanding Outflows

Abstract: Extensive modifications to the non-LTE radiative transfer code of Hillier have been made in order to improve the spectroscopic analysis of stars with stellar winds. The main improvement to the code is the inclusion of blanketing due to thousands of overlapping lines. To implement this effect, we have used the idea of super levels first pioneered by Anderson. In our approach, levels with similar excitation energies and levels are grouped together. Within this group, we assume that the departure coefficients are identical. Only the population (or equivalently, the departure coefficient) of the super level need be solved in order to fully specify the populations of the levels within a super level. Our approach is a natural extension of the single-level LTE assumption, and thus LTE is recovered exactly at depth. In addition to the line blanketing modifications, the code has been improved significantly in other regards. In particular, the new code incorporates the effect of level dissolution, the influence of resonances in the photoionization cross sections, and the effect of Auger ionization. Electron scattering with a thermal redistribution can be considered, although it is normally treated coherently in the comoving frame (which still leads to redistribution in the observer's frame). Several example calculations are described to demonstrate the importance of line blanketing on spectroscopic analysis. We find that the inclusion of blanketing modifies the strengths of some optical CNO lines in Wolf-Rayet (W-R) stars by factors of 2-5. In particular, the strengths of the WC classification lines C III λ5696 and C IV λ5805 are both increased because of iron blanketing. This should help alleviate problems found with nonblanketed models, which were incapable of matching the strengths of these lines. We also find that, in the UV (1100-1800 A), the influence of Fe is readily seen in both emission and absorption. The emission is sensitive to the iron abundance and should allow, for the first time, Fe abundances to be deduced in W-R stars. The improvements made to our code should greatly facilitate the spectroscopic analysis of stars with stellar winds. We will be able to determine the importance and influence of line blanketing, as well as of several other effects that have been included in the new code. It will also allow us to better determine W-R star parameters, such as luminosity, elemental abundances, wind velocity, and mass-loss rate. With future application to related objects, such as novae and supernovae, our new code should also improve our understanding of these objects with extended outflowing atmospheres.

Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma

Abstract: Background Dupilumab is a fully human anti–interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma. Methods We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed. Results The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among ...